Huntington's disease (HD) is one of at least nine autosomal dominant neurodegenerative diseases caused by the expansion of a glutamine repeat in disease proteins. A number of naturally occurring proteins have uninterrupted tracts of glutamine residues encoded by CAG triplet repeats. It now known that the expansion of the length of these uninterrupted tracts or regions of polyglutamine repeats in proteins is associated with specific neurodegenerative diseases. The expansion of polyglutamine tracts in proteins may become pathogenic if the polyglutamine tracts expand beyond a threshold length, which for most of the polyglutamine expansion-associated disorders is a length of approximately 35-40 residues. When the threshold is reached, the presence of the abnormal protein is associated with neurodegenerative diseases such as Huntington's disease (HD).
HD is an autosomal dominant neurodegenerative disorder caused by the expanded CAG tract in the huntingtin gene. HD is characterized clinically by progressive motor impairment, cognitive decline, and various psychiatric symptoms with the typical age of onset in the third to fifth decades. Postmortem changes in HD brains include neuronal loss and gliosis, particularly in the cortex and the striatum. (Vonsattel J P et al. J Neuropathol Exp Neurol. 57: 369-384, 1998.
The onset of Huntington's disease is characterized by choreic movements that result from the selective involvement of medium spiny neurons of the striatum. As HD progresses, more regions of the brain and spinal cord of the patient become involved. The severity of the symptoms and progression of HD varies from patient to patient, in part due to fact that the length of the expanded polyglutamine region correlates with the severity of the symptomatic presentation. The presence of a longer expanded polyglutamine repeat may indicate a more severe type of HD than the presence of a shorter expanded polyglutamine repeat. Thus, patients with longer expanded polyglutamine regions may have more severe clinical effects from the disease and may show an earlier age of onset than would patients with shorter expanded polyglutamine regions.
Previous studies in cell culture and animal models of HD have implicated histone acetyltransferase (HAT) and inhibitors of histone deacetylase (HDAC) as neuroprotective in HD, but the mechanism of protection remains unknown. Inhibitors of histone deacetylation (HDAC inhibitors) have shown promise as potential neuroprotective agents in cell culture and mouse models of HD. In addition, coactivators such as CREB-binding protein (CBP) that contain histone acetyltransferase activity (HAT) have also been shown to protect neurons from huntingtin-mediated toxicity. Mechanism of neuroprotection by compounds involved in acetylation in HD is completely unknown.
Although it is possible to diagnose HD, there are very limited treatment options available for patients diagnosed with HD. Additionally, it is not currently possible to adequately stage HD, to closely follow its onset, progression, or to monitor the effect of candidate therapeutic agents on HD. The lack of effective treatments for HD means that even with a definitive initial diagnosis, the therapeutic options are quite limited.